Localization of a non-syndromic X-linked mental retardation gene (MRX80) to Xq22-q24

Isolated mental retardation is clinically and genetically heterogenous and may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. We report here a linkage analysis in a large family including 15 members, 6 of whom presenting X-linked non-syndromic mental retardation (MRX). Two-point linkage analysis using 23 polymorphic markers covering the entire X chromosome demonstrated significant linkage between the causative gene and DXS8055 with a maximum LOD score of 2.98 at theta = 0.00. Haplotype analysis indicated location for the disease gene in a 23.1 cM interval between DXS1106 and DXS8067. This MRX localization overlaps with 7 XLMR loci (MRX23, MRX27, MRX30, MRX35, MRX47, MRX53, and MRX63). This interval contains two genes associated with non-syndromic mental retardation (NSMR), namely the PAK3 gene, encoding a p21-activated kinase (MRX30 and MRX47) and the FACL4 gene encoding a fatty acyl-CoA ligase (MRX63). As skewed X-inactivation, an apparently constant feature in FACL4 carrier females was not observed in an obligate carrier belonging to the MRX family presented here, the PAK3 gene should be considered as the strongest candidate for this MRX locus.     

Mapping of a gene for nonspecific X-linked mental retardation (MRX 75) to Xq24-q26

Nonspecific X-linked mental retardation is a heterogeneous condition consisting of nonsyndromal mental retardation in males. It is caused by mutation in one of several genes on the X chromosome (MRX genes). Here we report on the localization of a presumptive MRX gene to chromosomal region Xq24-q26 in a German family with nonspecific X-linked mental retardation (MRX 75, HUGO Human Gene Nomenclature Committee). Two point linkage analysis with 23 informative markers gave a lod score of 2.53 at theta = 0 for markers DXS425, DXS1254, DXS1114, and HPRT.     

Nonsyndromic X-linked mental retardation: mapping of MRX58 to the pericentromeric region.

An Austrian family with nonsyndromic X-linked mental retardation (MRX) is reported in which the obligatory carrier females are normal, and 5 affected males have mild to moderate mental retardation. Linkage analysis indicated an X pericentromeric localization, with flanking markers DXS989 and DXS1111 and a maximum multipoint LOD score of 2.09 (straight theta = 0) for the 7 cosegregating markers DXS1243, CybB, MAOB, DXS988, ALAS2, DXS991, and AR. MRX58 thus mapped within a 50-cM interval between Xp11.3 and Xq13.1 and overlapped with 23 other MRX families already described. This pericentromeric clustering of MRX families suggests allelism, with a minimum of 2 X-linked mental retardation (XLMR) genes in this region.     

A non-syndromal form of X-linked mental retardation (XLMR) is linked to DXS14

An analysis of the linkage of a non-syndromal form of X-linked mental retardation (MRX1) with a number of markers on the X chromosome was performed in a large pedigree. The affected males had moderate mental retardation; in all other clinical respects and cytogenetically they were normal. No recombinants were observed between the MRX1 gene and the marker DXS14 (p58.1) located at Xp11-cen (Z (max.) = 2.12 at theta = 0.00). Recombination was observed between the MRX1 gene and the markers DXS7 and DXYS1 which flank DXS14. This form of XLMR maps to the centromeric portion of the X-chromosome.     

A locus for nonspecific X-linked mental retardation mapped to a 22.3 cM region of Xp11.3-q22.3

By using several microsatellite markers scattered along the X chromosome, we studied a Chinese family with nonspecific X-linked mental retardation (MRX84) to search for a region including the MRX84 locus that was linked to the markers. Two-point linkage analysis demonstrated linkage between the disorder and several markers located at Xq22.2, with maximum LOD score Z(max) = 2.41 at recombination fraction theta = 0 for DXS1191 and DXS1230, respectively. Recombination events were observed with flanking markers DXS8080 and DXS456, located at Xp11.3 and Xq22.3, respectively, and a region of approximately 22.3 cM was defined. Accordingly, markers distal to Xp11.3 and Xq22.3 segregated independently of the disease. The localized region observed in this Chinese family overlaps with 29 other MRX loci previously reported in Xp11.3-q22.3. These results should contribute to the identification of the disease gene for the MRX84 disorder.     

Regional localization of a gene for nonspecific XLMR to Xp11.3-p11. 23 (MRX51) and tentative localization of an MRX gene to Xq23-q26.1.

Two families with nonspecific X-linked mental retardation (MRX) are presented. In the first family, MRX51, three male patients showed mild to borderline mental retardation. Multipoint linkage analysis yielded a maximal LOD score of 2.10 between markers DXS8012 and DXS1003, localizing the MRX51 gene at Xp11.3-p11.23. In the second family, XLMR7, three men showed moderate mental retardation (MR), and one possible female carrier had mild MR. Multipoint linkage analysis yielded an LOD score of 1.80 between markers DXS8063 and DXS1047, situating the disease gene at Xq23-q26.1. When the analysis was performed considering the affected female to be an expressing heterozygote carrier of the disease mutation, a maximal LOD score of 2.10 was found in the same region.     

MRX8: an X-linked mental retardation condition with linkage to Xq21.

A family in which 6 males have X-linked mental retardation has been studied with polymorphic DNA probes. The males differ from unaffected males only in impaired intellect and in smaller head size. The gene that causes mental retardation in the family appears to be located in band Xq21 on the basis of linkage with 3 markers: DXS250, DXS345 and DXS3 (theta max = 0.00; Zmax = 1.6). A multipoint lod score of 2.36 was obtain with no recombination relative to DXS326 in Xq21. This family is considered to have nonspecific X-linked mental retardation and has been given the designation MRX8.     

Mapping to distal Xq28 of nonspecific X-linked mental retardation MRX72: linkage analysis and clinical findings in a three-generation Sardinian family

Families with mentally retarded males found to be negative for FRAXA and FRAXE mutations are useful in understanding the genetic basis of X-linked mental retardation. According to the most recent data (updated to 1999), 69 MRX loci have been mapped and 6 genes cloned. Here we report on a linkage study performed on 20 subjects from a 4-generation Sardinian family segregating a non-specific X-linked recessive mental retardation (XLMR)(MRX72) associated with global delay of all psychomotor development. Five of 8 affected males have been tested for mental age, verbal and performance skills and behavioral anomalies; mental impairment ranged from mild to severe. Only minor anomalies were present in the affected subjects. Two-point linkage analysis based on 28 informative microsatellites spanning the whole X chromosome demonstrated linkage between the disorder and markers DXS1073 and F8c in Xq28 (maximum Lod score of 2. 71 at straight theta = 0.00). Multipoint linkage analysis confirmed the linkage with a Z(max) of 3.0 at straight theta = 0.00 at DXS1073 and F8c. Recombination in an affected male at DXS1073 and F8c allowed us to delimit centromerically and telomerically the region containing the putative candidate gene. The region, where MRX72 maps, overlaps that of another MRX families previously mapped to Xq28, two of which harbored mutations in GDI. Involvement of this gene was excluded in our family, suggesting another MRX might reside in Xq28.     

Localization of non-specific X-linked mental retardation gene (MRX73) to Xp22.2

Clinical and molecular studies are reported on a family (MRX73) of five males with non-specific X-linked mental retardation (XLMR). A total of 33 microsatellite and RFLP markers was typed. The gene for this XLMR condition was been linked to DXS1195, with a lod score of 2.36 at theta = 0. The haplotype and multipoint linkage analyses suggest localization of the MRX73 locus to an interval of 2 cM defined by markers DXS8019 and DXS365, in Xp22.2. This interval contains the gene of Coffin-Lowry syndrome (RSK2), where a missense mutation has been associated with a form of non-specific mental retardation. Therefore, a search for RSK2 mutations was performed in the MRX73 family, but no causal mutation was found. We hypothesize that another unidentified XLMR gene is located near RSK2.     

A gene for nonspecific X-linked mental retardation (MRX41) is located in the distal segment of Xq28

We report on a family in which non-syndromal mild to moderate mental retardation segregates as an X-linked trait (MRX41). Two point linkage analysis demonstrated linkage between the disorder and marker DXS3 in Xq21.33 with a lod score of 2.56 at θ = 0.0 and marker DXS1108 in Xq28 with a lod score of 3.82 at θ = 0.0. Multipoint linkage analysis showed that the odds for a location of the gene in Xq28 vs Xq21.33 are 100:1. This is the fourth family with non-specific X-linked mental retardation with Xq28-qter as the most likely gene localization. © 1996 Wiley-Liss, Inc.     

Nonsyndromic X-linked mental retardation: Mapping of MRX58 to the pericentromeric region

An Austrian family with nonsyndromic X-linked mental retardation (MRX) is reported in which the obligatory carrier females are normal, and 5 affected males have mild to moderate mental retardation. Linkage analysis indicated an X pericentromeric localization, with flanking markers DXS989 and DXS1111 and a maximum multipoint LOD score of 2.09 (θ = 0) for the 7 cosegregating markers DXS1243, CybB, MAOB, DXS988, ALAS2, DXS991, and AR. MRX58 thus mapped within a 50-cM interval between Xp11.3 and Xq13.1 and overlapped with 23 other MRX families already described. This pericentromeric clustering of MRX families suggests allelism, with a minimum of 2 X-linked mental retardation (XLMR) genes in this region. Am. J. Med. Genet. 86:102–106, 1999. © 1999 Wiley-Liss, Inc.     

Localization of MRX82: a new nonsyndromic X-linked mental retardation locus to Xq24-q25 in a Basque family

Clinical and molecular studies are reported on a Basque family (MRX82) with nonsyndromic X-linked mental retardation (XLMR) in five affected males. A total of 38 microsatellite markers were typed. The XLMR locus has been linked to DXS8067, DXS1001, DXS425, DXS7877, and DXS1183 with a maximum LOD score of 2.4. The haplotype studies and multipoint linkage analysis suggest a localization of the MRX82 locus to an interval of 7.6 Mb defined by markers DXS6805 and DXS7346, in Xq24 and Xq25, respectively. No gene contained in this interval has been so far associated with nonsyndromic mental retardation, except for GRIA3, disrupted by a balanced translocation in a female patient with bipolar affective disorder and mental retardation. However, the search for mutations of this gene did not showed a pathogenic mutation in the present family. Given that there are other eight MRX families overlapping this interval, none of them with known mutation, we conclude that at least one new gene responsible for nonsyndromic mental retardation is located in this region.     

Linkage studies with the gene for an X-linked syndrome of mental retardation, microcephaly and spastic diplegia (MRX2)

A family in which a gene (MRX2) is segregating for an X-linked syndrome of mental retardation, short stature, microcephaly, brachycephaly, spastic diplegia, small testes and possible intra-uterine growth retardation is described. There are 7 clearly affected males and one possibly affected infant in the family. The obligate carriers are normal. Linkage studies show a suggestion of linkage to loci near the centromere. The maximum lod score was 2.10 at theta = 0.11 for DXYS1, assuming the possibly affected male carried the MRX2 gene. There were lower lod scores suggestive of linkage with DXS7 (theta = 0.14; z = 1.29) and DXS94 (theta = 0.11; z = 1.22).     

Gene for apparently nonsyndromic X-linked mental retardation (MRX32) maps to an 18-Mb region of Xp21.2-p22.

We studied a family with 11 males having X-linked mental retardation (XLMR) using microsatellite markers. Aside from the mental retardation, the affected males do not appear to differ from their unaffected brothers or uncles. The gene for this XLMR condition has been linked to DXS451 in Xp22.13 with a lod score of 5.18 at straight theta = 0. Recombination was detected at DXS992 (Xp21.3) and DXS1053 (Xp22.2), thereby defining the limits of the localization. This family is considered to have nonsyndromic XLMR and has been assigned the designation MRX32.     

A gene for nonsyndromic X-linked mental retardation (MRX77) maps to Xq12-Xq21.33

Nonsyndromic X-linked mental retardation (MRX) is a highly heterogeneous condition in which mental retardation appears to be the only consistent manifestation. According to the most recent data, 77 MRX families with a lod score of >2 have been mapped and eight genes have been cloned. We hereby report on a linkage analysis performed on a Greek family with apparently nonsyndromic MRX. The affected males have moderate to severe mental retardation, severe speech problems, and aggressive behavior. Two-point linkage analysis with 26 polymorphic markers spanning the entire X chromosome was carried out. We could assign the causative gene to a 27 Mb interval in Xq12-Xq21.33. The maximum LOD score was found for markers DXS1225, DXS8114, and DXS990 at 2.36, 2.06, 2.06, respectively at theta = 0.00. Recombination was observed for DXS983 at the proximal side and DXS6799 at the distal side. Nineteen other MRX families have been described with a partial overlapping disease gene interval in proximal Xq. No mutations were found in the MRX77 family for three known or candidate MRX genes, from this region OPHN1, RSK4, and ATR-X. These data indicate that the Xq12-Xq21.33 interval contains at least one additional MRX gene.     

X-linked mental retardation, short stature, microcephaly and hypogonadism maps to Xp22.1-p21.3 in a Belgian family

X-linked mental retardation (XLMR) is a heterogeneous disorder that can be classified as either non-specific (MRX), when mental retardation is the only feature, or as syndromic mental retardation (MRXS). Genetic defects underlying XLMR are being identified at a rapid pace, often starting from X-chromosomal aberrations and XLMR families with a well-defined linkage interval. Here, we present a new family with a syndromic form of XLMR, including mild mental retardation, short stature, microcephaly and hypogonadism. Two-point linkage analysis with 24 polymorphic markers spanning the entire X chromosome was carried out. We could assign the causative gene to a 6 cM interval in Xp22.1-p21.3, with a maximum LOD score of 2.61 for markers DXS989 and DXS1061 at theta = 0.00. No mutations were found in the presented family for two known MRX genes mapping to this interval, ARX and IL1RAPL-1. These data indicate that the interval Xp22.1-p21.3 contains at least one additional MRXS gene.     

Regional localization of two genes for nonspecific X-linked mental retardation to Xp22.3–p22.2 (MRX49) and Xp11.3–p11.21 (MRX50)

Two families with nonspecific X-linked mental retardation (XLMR) are presented. In the first family, MRX49, 5 male patients in 2 generations showed mild to moderate mental retardation. Two-point linkage analysis with 28 polymorphic markers, dispersed over the X-chromosome, yielded a maximal LOD score of 2.107 with markers DXS7107 and DXS8051 at θ = 0.0, localizing the MRX49 gene at Xp22.3-p22.2, between Xpter and marker DXS8022. Multipoint linkage analysis showed negative LOD values over all other regions of the chromosome. In the second family, MRX50, 4 males in 2 generations showed moderate mental retardation. Pairwise linkage analysis with 28 polymorphic markers yielded a LOD score of 2.056 with markers DXS8054, DXS1055, and DXS1204, all at θ = 0.0. Flanking markers were DXS8012 and DXS991, situating the MRX50 gene at Xp11.3-Xp11.21, in the pericentromeric part of the short arm of the X chromosome. Am. J. Med. Genet. 73:474–479, 1997. © 1997 Wiley-Liss, Inc.     

Regional localization of two MRX genes to Xq28 (MRX28) and to Xp11.4-Xp22.12 (MRX33)

Two genes responsible for a nonspecific form of X-linked mental retardation (MRX28 and MRX33) were localized by linkage analysis with 40 highly polymorphic DNA markers situated along the entire the X chromosome. In family 1, the gene could be mapped within a 14-cM interval at Xq28, distal to the recombining marker DXS1113 (MRX28). The maximum LOD score was 2.75, with DXS52 at ϕ = .0. In family 2, the gene was localized within a 30-cM interval at Xp11.4-22.12 between the recombining markers DXS365 and MAOB, including the DMD gene (MRX33). Maximum LOD scores of 2.82 were obtained with markers DMD-STR49, DMD-DysII, CYBB, and DXS1068. © 1996 Wiley-Liss, Inc.     

X-linked mental retardation syndrome with characteristic "coarse" facial appearance, brachydactyly, and short stature maps to proximal Xq.

We describe a three-generation family in which X-linked mental retardation (XLMR) is associated with minor facial anomalies and brachydactyly. Two brothers and four nephews have "coarse" facial appearance, brachydactyly with widening of the distal phalanges, short stature, and moderate mental retardation. The three obligate carrier women have normal intelligence and normal physical findings. The results of linkage analysis carried out in 1988 using restriction fragment length polymorphisms (RFLPs) were suggestive of linkage to DXYS1 and DXS101 in proximal Xq (Zmax = 1.63 at straight thetamax = 0.0) [Carpenter et al., 1988: Am J Med Genet 43:A139]. The family was restudied with 16 microsatellite loci from Xp11.4 through Xq24. Linkage analysis demonstrated significant linkage to DXS1003, ALAS2, AR, DXS986, DXS990, DXS454, DXS1106, DXS1105, and DXS1220 from Xp11.3 to Xq23 (Zmax = 2.53 at straight thetamax = 0.0). Recombinations detected between MAOB and DXS1055 and between DXS1220 and DXS1001 place the disease locus between Xp11.3 and Xq23. Among the genes known to map to this region is the XNP gene for the alpha-thalassemia/mental retardation syndrome (ATR-X). This fact, along with the phenotypic similarity between our patients and ATR-X males, led us to consider XNP as a candidate gene for this family. X-inactivation studies provided further evidence for the involvement of XNP by showing completely skewed X-inactivation patterns in the three obligate carrier females, a pattern characteristic of carriers of XNP mutations.     

Localization of a gene for X-linked nonspecific mental retardation (MRX24) in Xp22.2–p22.3

Nonspecific X-linked mental retardation (MRX) includes several distinct genetic entities in which mental retardation is not associated with additional distinguishing physical changes. We report linkage data in a Spanish family with MRX, using polymorphic DNA markers distributed over the X chromosome. Two-point linkage analysis demonstrated close linkage between the MRX locus and DXS85 in Xp22.3 with a peak lod score of 2.28 at a Ø = 0.00. Analysis of multiple informative meioses suggested a localization of the MRX locus (MRX24) between DXS278 and DXS207. Multipoint linkage analysis resulted in a maximum LOD score of 2.45 at 3 cM proximal to DXS85, and allowed us to reject a localization of the MRX24 gene in all other regions from Xp21–Xqter. These findings localize the MRX24 gene in the chromosomal region Xp22.2–p22.3. © 1995 Wiley-Liss, Inc.